Allergy to dust mites affects populations in most parts of the world. The most common dust mites are the European house dust mite (Dermatophagoides pteronyssinus) and the American house dust mite (Dermatophagoides farinae), which contain the major allergens Der p 1/Der p 2 and Der f 1/Der f 2, respectively. Other common dust mites are found in subtropical/tropical regions around the world, for example Blomia tropicalis containing the major allergens Blo t 1 and Blo t 2 and Euroglyphus maynei containing the major allergens Eur m 1 and Eur m 2.
Today, the treatment of dust mite allergy is performed with allergen-specific immunotherapy products based on whole, intact or modified allergens typically administered as a complex extract made from dust mites. Typically, such products are administered by subcutaneous injection or by the sublingual route to a subject over an extended period of time, frequently months or years and are now appreciated to induce a state of “tolerance” in the subject. The mechanism of action is thought to involve induction of IgG inhibitory antibodies, suppression of mast cell/basophil reactivity, suppression of T-cell responses, the promotion of T-cell anergy, and/or clonal deletion, and in the long term, decrease in the levels of allergen specific IgE.
Unfortunately, allergen-specific immunotherapy bears the risk of IgE-mediated adverse events including serious anaphylactic responses. Therefore, this therapy is not as widely offered to allergic subjects as its beneficial effect actually justifies. In the recent years, it has been suggested to treat allergy using smaller fragments (peptides) of the primary amino acid sequence of allergens (e.g. of the major allergens), that contain one or more epitope(s) recognized by T cells regulating the allergic reaction. This concept has been termed peptide immunotherapy (PIT), in which, repeated doses of the peptide is administered, typically by intradermal injection, to a subject (Moldaver and Larche 2011).
More specifically on the molecular level, peptides are bound by Human Leucocyte Antigen (HLA) class II on the surface of Antigen Presenting Cells (APC). This peptide-HLA complex is then recognized by specific T-cell receptors on the cell surface of T-cells that upon interaction with the APCs becomes activated. A major difference of peptide-based immunotherapy and therapies based on full-length allergens is that this interaction is thought to occur without a concomitant antibody mediated “danger signal” being elicited. This is thought to drive the T-cell response in a more tolerogenic direction.
Peptide-based immunotherapy (PIT) represents a potentially attractive alternative to allergen extracts, with a more favorable safety/tolerability profile and a significantly shorter treatment regimen than existing therapies. In contrast to therapies based on intact allergens, PIT solely addresses the T-cell compartment of the immune system without engaging existing antibody responses because of the lack of antibody epitopes due to the smaller size of peptides compared to allergens. Consequently, no IgE-mediated adverse events are expected although they are often seen when treating allergy with traditional allergen-based immunotherapy products. Peptide immunotherapy is today in clinical development and does seem to have a favorable safety profile over the whole-allergen based vaccines.
A shortcoming of using the T cell epitope-containing peptides is, however, associated with the restriction of each peptide to only bind a subset of the naturally occurring HLA Class II molecules within the human population. A mix of several peptides covering different HLA Class II alleles is therefore mandatory to generate a broadly acting immunotherapy allergy treatment. As this repertoire of HLA Class II alleles varies from one person to another and from one ethnic population to another, it is challenging to provide peptide-based immunotherapies that can be offered to allergic subjects of any geographic region in the world unless numerous peptides are included in the vaccine. Taken into consideration the enormous costs and risks in the clinical development of new vaccines and the increasing demands from regulatory bodies to meet high standards for toxicity testing, dose justification, safety and efficacy trials, it is desirable to provide peptide vaccines containing as few peptides as possible, but at the same time to be able to treat the majority of dust mite allergic subjects in a worldwide population with the same immunotherapy product.
Such a product should comprise a combination of peptides that in combination are able to bind the worldwide HLA Class II allele repertoire, and the resulting peptide-HLA complexes should be recognized as T cell epitopes in the subject so as to induce tolerogenic immunological reactions. Recent studies in mice have indicated that peptide immunotherapy using one peptide alone did not reduce the severity of allergic airway inflammation, but that it is at least required that the mice are treated with two peptides that match the MHC molecules of the mice being treated (Mackenzie K J et al 2013).
International patent applications WO93/08280, WO94/24281, WO95/28424, WO2009/022156, WO95/28424 and WO2010/018384, respectively, and US application US20130302338 relate to peptides of house dust mite allergens and their use in treating house dust mite allergy.